Although obesity is associated with a variety of chronic health conditions, excess deposition of visceral adipose tissue (VAT) is more consistently associated with metabolic abnormalities (diabetes and dyslipidemia) and cardiovascular disease (CVD), even in non-obese older adults. Excess VAT is postulated to underlie clustered metabolic risk factors including dyslipidemia, elevated blood pressure and high plasma glucose. The overall goal of this project is to identify genetic determinants of visceral adiposity. A staged approach is designed to move from a genome wide association (GWA) study - nested in the Health Aging and Body Composition (Health ABC) Study - to replication of the most promising SNPs in five similarly-phenotyped (computed tomography (CT)-measured VAT) independent studies. Specifically, the following two aims are proposed. Aim 1: To determine the association between common single nucleotide polymorphisms (SNPs) and CT-measured VATamong a total sample of 2,400 subjects from the Health ABC study (1200 randomly selected European Americans (EA) and 1200 African Americans (AA)). The 1200 EAs and1200 AAs will be genotyped using Illumina 550K and 650K chips, respectively. SNPs will be rank-ordered using an algorithm incorporating statistical significance, prior genomic evidence (e.g., linkage studies), and other indicators of priority (e.g., potential functional significance) to identify the most promising 768 VAT-associated SNPs for each ethnic group. Aim 2: To confirm or refute most promising VAT-associated SNPs from Health ABC in five independent replication cohorts using two-stage sequential design. In Stage I, Two cohorts, the Framingham Heart study (FHS, 3329 EAs) and Jackson Heart study (JHS, 4605 AAs), will be used to follow up the promising 768 VAT- associated SNPs for EAs and AAs from Heath ABC, respectively. In stage II, three other cohorts, the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik, 5764 EAs) Study, the Multi-Ethnic Study of Atherosclerosis (MESA, 787 EAs, 411 AAs A), and the Insulin Resistance Atherosclerosis Family Study (IRAS, 600 AAs), will be used to further validate those SNPs (probably 10-15) replicated in FHS or JHS. In addition, the available GWA studies (e.g. FHS and MESA SHARe and future others) will allow for direct in silico replication and prospective meta-analysis of SNPs captured either directly or through LD (r2e0.8) based on data from the HapMap project. In aggregate, the proposed study provides a unique opportunity to discover genes (and their variants) involved in visceral fat accumulation and may provide novel insights into the pathophysiology, prevention and promising therapeutic targets for a number of obesity-related disorders. PUBLIC HEALTH RELEVANCE: The amount of fat in the abdomen is associated with diabetes, abnormal cholesterol, and heart disease. We propose studying genetic factors that determine the amount of fat in the abdomen. Identification of these genetic factors may help to determine, at a relatively early age, who is at risk of fat related diseases and needs aggressive treatment to prevent the fat related diseases.